Mucociliary clearance is an important defense mechanism of the human airways and middle/inner ear tract. Coordinated beats of cilia in the airways and ears propel the mucous layer toward the pharynx, carrying along with it microorganisms and other particles captured in the mucus. Normal function of this system depends on the frequency and coordination of ciliary beating and the properties of the mucus itself.
It has been discovered that extracellular nucleoside triphosphates, especially UTP, modulate mucociliary clearance. Specifically, UTP stimulates ciliary beat frequency (D. Drutz, et al., Drug Development Research, 377(3), 185, (1996)), increases hydration of the mucous layer on the luminal surface of the airway (R. Boucher, et al., Adenosine and Adenine Nucleotides: From Molecular Biology to Integrative Physiology, p. 525-32 "Mechanisms and Therapeutic Actions of Uridine Triphosphates in the Lung" (L. Belardinelli, et al. ed., Alumwer Academic Publishers, Boston, 1995)), and increases mucin release from goblet cells and submucosal glands (M. I. Lethem, et al., Nucleotide regulation of goblet cells in human airway epithelial explants: normal exocytosis in cystic fibrosis. Am. J. Respir. Cell Mol. Biol., 1993; 9:315-322. In addition, UTP and other nucleotides have been shown to stimulate the release of surfactant phospholipids from type II alveolar cells (S. Rooney, et al., Progr. Respir. Res., 27, 84-91 (1994); L. Gobran, et al., Am. J. Physiol., 267, L625-33 (1994). It has been postulated that UTP is effective in the treatment of cystic fibrosis and other airway diseases involving retained mucous secretions as described in U.S. Pat. No. 5,292,498 and U.S. Pat. No. 5,420,116. It has also been demonstrated that UTP is safe and improves cough clearance in PCD patients (P. Noone, et al., Am. J. Resp. Crit Care Med A530, (1996)). Inspire Pharmaceuticals, Inc. (Durham, N.C.) studies have demonstrated that UTP helps induce a sputum sample by hydrating mucous secretions and stimulating ciliary beat frequency for diagnostic analysis, such as cytopathology for lung cancer or acid-fast bacillus for tuberculosis. It is likelly that UTP decreases the risk of retained secretions in patients who are immobilized or receiving mechanical ventilation, thereby preventing pneumonia, including ventilator-associated pneumonia (VAP).
A UTP formulation under the tradename Uteplex.RTM., with a pH of 9.0, has been marketed in France by Wyeth for the treatment of lower backpain. The French biotechnology company Synthelabo has developed a formulation of adenosine triphosphate (ATP) under the tradename rhinATP.TM. for the treatment of nasal mucous fluid congestion. Belgium Patent No. 597,360, issued Dec. 14, 1960, entitled "Novel Therapeutic Composition Usable as a Muscle and Nerve Stimulant", describes a formulation of UTP used in various myopathies and in nerve stimulation therapy.
With the prospect of increasing clinical uses of UTP on the horizon, the need for more biocompatible and less temperature sensitive formulations has emerged.
Formulation I of the present invention differs from prior art nucleotide pharmaceutical formulations in that it is sterilized by filtration rather than by heat, it has a controlled tonicity within the osmolarity range of 250 to 1000 mOsM, most preferably approximately 300 mOsM, and it is pH-adjusted to give values in the range of 6.5 to 8.5, preferably 6.5 to 8.0 and most preferably 7.0 to 7.5. An unexpected property of the present invention is that the Formulation I is capable of extended shelf-life if kept properly refrigerated. This novel UTP Formulation I is compatible for use in a commercially available nebulizer (e.g., jet nebulizers, ultrasonic nebulizers, etc.) which facilitate their administration in the clinical setting. The liquid UTP Formulation I of the present invention may be delivered to the airways of a patient via inhalation of a nebulized form or it may be delivered to the nose, eye, sinuses or middle/inner ears by means of nasal, eye or ear drops. In either the nebulized or liquefied forms, an effective amount of UTP contacts the affected site directly.
Formulation II of the present invention differs from prior art nucleotide formulations in that it is particularly well-suited for administration via small, portable hand-held devices that are capable of efficiently generating fine respirable aqueous based aerosols from small pre-measured volumes or metering a small volume from a liquid reservoir prior to administration. Suitable devices for the administration of Formulation II include, but are not limited to, those currently in development by the Aradigm Corporation (Hayward, Calif.) as disclosed in U.S. Pat. No. 5,544,646 by Aerogen, formerly Fluid Propulsion Technology as disclosed in U.S. Pat. No. 5,164,740, and by the Technology Partnership (Hertfordshire, UK) as disclosed in U.S. Pat. No. 5,518,179. In addition, small volume topical delivery metered pump based systems, such as that patented by Bespak plc, UK disclosed in U.S. Pat. No. 5,547,131, may be used to deliver Formulation II of the present invention via the nose or ear.